TIMI

The Thrombolysis In Myocardial Infarction, or TIMI Study Group, is an Academic Research Organization (ARO) affiliated with Brigham and Women's Hospital and Harvard Medical School dedicated to advancing the knowledge and care of patients with cardiovascular disease. The TIMI Study Group provides robust expertise in the key aspects of a clinical trial, including academic leadership, global trial management, biostatistics, clinical event adjudication, safety desk, medical hotline, and core laboratories. The group has its headquarters in Boston, Massachusetts.

The TIMI Study Group was founded by Eugene Braunwald, MD in 1984. Dr. Braunwald held the chairmanship until 2010, when he appointed Marc Sabatine, MD, MPH to the position. The group has conducted over 70 practice-changing clinical trials in patients with cardiovascular disease or risk factors for cardiovascular disease. Among the group's most important contributions to medicine is the TIMI Risk Score, which assess the risk of death and ischemic events in patients experiencing unstable angina (UA) or a non-ST elevation myocardial infarction (NSTEMI).

TIMI Trials

Past Trials

TIMI 1 compared the efficacy of tissue plasminogen activator and streptokinase for reperfusion of the infarct-related artery in ST elevation myocardial infarction.

TIMI 2A compared the results of 3 strategies of coronary angiography and angioplasty following intravenous thrombolytic therapy for ST elevation myocardial infarction: immediate invasive, delayed invasive (18-48 h), and a conservative strategy.

TIMI 2B compared the effects of an invasive vs. conservative strategy following thrombolysis with rtPA among patients with ST elevation myocardial infarction, and the effect of immediate vs. delayed (6 days) metoprolol therapy among patients with ST elevation myocardial infarction treated with rtPA (a substudy of the TIMI II trial).

TIMI 3A evaluated the effect of rtPA vs. placebo on the culprit coronary lesion in patients with unstable angina or non-Q-wave myocardial infarction.

TIMI 3 Registry was an observational study to enumerate and investigate the natural history and response to treatment of patients presenting with unstable angina and non-Q-wave myocardial infarction.

TIMI 4 compared the efficacy of front loaded tPA vs. APSAC vs. the combination of reduced dose tPA and APSAC for treatment of patients presenting within 6 hours of onset of ST elevation myocardial infarction.

TIMI 5 evaluated the safety and efficacy of several doses of hirudin vs. unfractionated heparin in combination with front-loaded tPA for the treatment of patients presenting with ST elevation myocardial infarction.

TIMI 6 compared three doses of hirudin vs. unfractionated heparin in combination with streptokinase for patients with ST elevation myocardial infarction.

TIMI 7 evaluated the safety and efficacy of several doses of hirulog in comparison with unfractionated heparin for the treatment of unstable angina.

TIMI 8 compared the efficacy of hirulog with unfractionated heparin for the treatment among patients presenting with unstable angina and non-Q-wave myocardial infarction.

TIMI 9A compared the safety and efficacy of intravenous hirudin to unfractionated heparin as adjunctive therapy to fibrinolysis and aspirin among patients presenting with ST elevation myocardial infarction.

TIMI 9B compared the efficacy of a lower dose of intravenous hirudin to unfractionated heparin as adjunctive therapy to fibrinolysis and aspirin among patients presenting with ST elevation myocardial infarction.

TIMI 9 Registry assessed management strategies and outcomes of patients presenting with ST elevation myocardial infarction in the era of aggressive reperfusion strategies, who were ineligible for fibrinolytic therapy.

TIMI 10A evaluated the pharmacokinetics, safety and efficacy of several doses of TNK-tPA among patients presenting with acute ST elevation myocardial infarction.

TIMI 10B compared the angiographic efficacy and safety of several doses of TNK with front loaded rtPA for the treatment of ST elevation myocardial infarction.

ASSENT I-(TIMI 10C) compared the safety of several doses of TNK-tPA with rtPA for the treatment of ST elevation myocardial infarction.

TIMI 11A compared the safety and tolerability of two weight-adjusted regimens of subcutaneous injections of enoxaparin among patients presenting with unstable angina or non-Q-wave myocardial infarction.

TIMI 11B evaluated the safety and efficacy of subcutaneous enoxaparin compared with unfractionated heparin for the treatment of patients presenting with unstable angina or non-Q-wave myocardial infarction.

TIMI 12 evaluated the safety and efficacy of the oral GP IIb/IIa inhibitor sibrafiban for the treatment of patients with a recent acute coronary syndrome.

TIMI 14 evaluated the benefit of abciximab bolus plus 12 hour infusion alone or in conjunction with reduced dose thrombolytic therapy among patients presenting with ST elevation myocardial infarction.

TIMI 15A evaluated the pharmacodynamic response, safety and pharmacokinetics of various doses of the GP IIb/IIIa inhibitor RPR 109891 given intravenously for the treatment of patients with acute coronary syndromes.

TIMI 15B evaluated the pharmacodynamic response, safety and pharmacokinetics of the GP IIb/IIIa inhibitor RPR 109891 given intravenously followed by oral administration for the treatment of patients with acute coronary syndromes.

OPUS-TIMI 16 evaluated if an oral GP IIb/IIIa inhibitor, orbofiban, reduces major cardiovascular events for the treatment of patients with an unstable coronary syndrome within 72 hours.

InTIME II-TIMI 17 compared the single-bolus fibrinolytic agent lanoteplase (nPA) with accelerated rtPA for the treatment of patients with ST elevation myocardial infarction.

TACTICS-TIMI 18 compared invasive vs. conservative strategies among patients presenting with unstable angina and non-Q-wave myocardial infarction following treatment with the glycoprotein IIb/IIIa inhibitor tirofiban.

ER-TIMI 19 evaluated the safety and feasibility of prehospital fibrinolysis with reteplase for the treatment of patients with ST elevation myocardial infarction.

INTEGRITI-(TIMI 20) evaluated the safety and efficacy of the combination of eptifibatide and TNK among patients presenting with ST elevation myocardial infarction.

A to Z-(TIMI 21) evaluated if early aggressive treatment with simvastatin compared to standard therapy reduces major cardiac events at 1 year in high-risk acute coronary syndrome patients. TIMI 21 also evaluated the safety and efficacy of enoxaparin compared to unfractionated heparin when given to patients with acute coronary syndromes also receiving the GP IIb/IIIa inhibitor tirofiban.

PROVE IT-TIMI 22 compared the efficacy of atorvastatin vs. pravastatin and the clinical efficacy of the antibiotic gatifloxacin vs. placebo in a 2 x 2 factorial design among patients presenting with unstable angina or non-Q-wave myocardial infarction.

ENTIRE-TIMI 23 assessed the safety and efficacy of enoxaparin as an adjunct to thrombolysis with or without GP IIb/IIIa therapy among patients presenting with ST elevation myocardial infarction.

FASTER-(TIMI 24) evaluated the efficacy and safety of reduced dose TNK-tPA in combination with tirofiban bolus and infusion compared to a control group of full dose TNK-tPA.

EXTRACT-TIMI 25 evaluated the efficacy and safety of enoxaparin throughout the index hospitalization or unfractionated heparin for at least 48 hours in patients with ST-elevation myocardial infarction scheduled to undergo fibrinolysis.

JUMBO-TIMI 26 evaluated the efficacy and safety of prasugrel, a novel thienopyridine, compared to clopidogrel in patients undergoing PCI.

PROXIMATE-TIMI 27 evaluated the safety and hemostatic effects of a monoclonal antibody to tissue factor in patients with stable coronary disease.

CLARITY-TIMI 28 assessed the efficacy and safety of adding clopidogrel to a standard fibrinolytic regimen that includes aspirin.

ADVANCE MI-(TIMI 29) evaluated the efficacy and safety of facilitated PCI following the combination of reduced dose TNK-tpa and eptifibatide compared to primary PCI with eptifibatide alone.

PROTECT-TIMI 30 evaluated the angiographic efficacy of bivalirudin vs eptifibatide for coronary stenting.

TIMI 31 evaluated the efficacy, safety, and pharmacokinetics of a novel fibrinolytic agent, BB-10153, in patients with ST-elevation myocardial infarction.

ANTHEM-TIMI 32 assessed the efficacy and safety of anticoagulation with rNAPc2 in non-ST segment elevation acute coronary syndrome patients managed with an early invasive strategy.

DISPERSE2-TIMI 33 evaluated the safety, tolerability, and efficacy of AZD6140, an oral reversible ADP receptor antagonist, compared with clopidogrel in patients with non-ST segment elevation acute coronary syndrome.

TITAN-TIMI 34 evaluated initiation of eptifibatide in the emergency department versus at the time of percutaneous intervention for patients with ST-elevation myocardial infarction.

PROMPT-TIMI 35 evaluated novel protein markers of ischemia using proteomic testing in a prospective cohort of patients with stable coronary disease undergoing exercise stress testing.

MERLIN-TIMI 36 evaluated a novel anti-ischemic agent, ranolazine, in patients with acute coronary syndromes.

TIMI 37A evaluated the efficacy, safety, and pharmacokinetics of INO-1001, a poly(ADP-ribose) polymerase in patients with ST-segment elevation myocardial infarction.

TRITON-TIMI 38 evaluated prasugrel compared with clopidogrel in patients with acute coronary syndromes.

EARLY ACS-(TIMI 39) assessed the clinical benefits of early front-loaded eptifibatide in the treatment of patients with non-ST segment elevation acute coronary syndrome.

IMPROVE-IT (TIMI 40) determined whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups provided data on whether the target for LDL-C lowering should be reduced further.

PLATO evaluated ticagrelor compared with clopidogrel in patients with acute coronary syndromes.

SEPIA-ACS-TIMI 42 evaluated the efficacy and safety of otamixaban, a direct factor Xa inhibitor, in patients with non-ST-elevation acute coronary syndrome.

AVANT GARDE-TIMI 43 was a proof of concept trial to evaluate the efficacy of early RAAS inhibition with aliskiren (a renin antagonist), valsartan, or their combination in lowering natriuretic peptides in patients with acute coronary syndromes.

PRINCIPLE-TIMI 44 compared prasugrel versus higher loading and maintenance doses of clopidogrel for inhibiting platelet aggregation in patients undergoing elective percutaneous intervention.

ATLAS ACS-TIMI 46 compared the safety and efficacy of rivaroxaban, an oral direct factor Xa inhibitor, to placebo in patients with acute coronary syndromes.

ENGAGE AF-TIMI 48 demonstrated the safety and efficacy profile, in two different dose regimens of DU-176b, (an investigational new drug being tested for the prevention of stroke/systemic embolic events (SEE)), in individuals with atrial fibrillation. Patients were randomized to one of three treatment groups: High Dose Regimen, Low Dose Regimen, & Warfarin.

TRA 2°P-TIMI 50 was designed to determine whether SCH 530348, when added to the existing standard of care for preventing heart attack and stroke (e.g., aspirin, clopidogrel) in patients with a known history of atherosclerosis, will yield additional benefit over the existing standard of care without SCH 530348 in preventing heart attack and stroke.

ATLAS ACS 2-TIMI 51 was a phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating an oral, direct factor Xa inhibitor (rivaroxaban) in subjects following an acute coronary syndrome.

SOLID-TIMI 52 was a randomized, double-blind, placebo-controlled trial to assess the efficacy of darapladib, a novel Lp-PLA2 inhibitor, when added to standard of care in high-risk patients stabilized after ACS.

SAVOR-TIMI 53 was a randomized, double-blind, placebo-controlled trial to assess the cardiovascular efficacy and safety of saxaglipitin, a DPP-4 inhibitor, when added to standard of care in patients with type 2 diabetes mellitus.

PEGASUS–TIMI 54 was a randomized, double-blind, placebo-controlled trial to assess the prevention of thrombotic events with ticagrelor on a background of aspirin therapy in patients with history of myocardial infarction.

HPS3/TIMI 55 REVEAL assessed the effect of cholesterol ester transfer protein (CETP) inhibition with anacetrapib 100 mg versus matching placebo on time to first major coronary event among 30,000 individuals with pre-existing vascular disease.

ELEVATE-TIMI 56 assessed whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.

LAPLACE-TIMI 57 assessed whether 12 weeks of therapy with a novel injectable monoclonal antibody against PCSK9, given on a background of statin therapy, will be safe and to what degree it will reduce LDL-cholesterol in hypercholesterolemic subjects.

DECLARE-TIMI 58 was a superiority trial and designed to test the hypothesis that in patients with type 2 diabetes mellitus long-term treatment with dapagliflozin, an oral sodium glucose cotransporter 2 (SGLT2) inhibitor, will reduce one or both of the co-primary endpoints: (1) the incidence cardiovascular death, myocardial infarction, or ischemic stroke or (2) the incidence of cardiovascular death or hospitalization for heart failure.

FOURIER (TIMI 59)/EBBINGHAUS - FOURIER assessed the Impact of additional LDL-cholesterol reduction on major cardiovascular events when AMG 145 is used in combination with statin therapy in patients with clinically evident cardiovascular disease. EBBINGHAUS was a cognitive study of patients enrolled in the FOURIER trial.

LATITUDE-TIMI 60 assessed whether losmapimod can safely reduce the risk of a subsequent cardiovascular event when started immediately after ACS.

PIONEER-HF evaluated the effect of sacubitril and valsartan (LCZ696) versus enalapril on changes in NT-proBNP and safety and tolerability of in-hospital initiation of LCZ696 compared to enalapril in HFrEF patients who have been stabilized following hospitalization for acute decompensated heart failure (ADHF).

CAMELLIA-TIMI 61 was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with CV disease and/or multiple CV risk factors.

Current Trials

VESALIUS-CV will assess the effect of lowering low-density lipoprotein cholesterol (LDL-C) with evolocumab on major cardiovascular events in adults without a prior myocardial infarction (MI) or stroke who are at high risk of a cardiovascular event.

REAL-TIMI 63B is a Phase 2b randomized, blinded, placebo controlled study to evaluate the efficacy, safety, PK/pharmacodynamic, and immunogenicity of repeat doses of MEDI6012 in adult subjects presenting with acute STEMI (ST segment elevation myocardial infarction).

HPS-4/TIMI 65 ORION-4 will examine the effects of inclisiran, a small interfering RNA (siRNA) that inhibits the synthesis of PCSK9, on cardiovascular outcomes among individuals with atherosclerotic cardiovascular disease. It will be conducted at high-enrolling sites using a streamlined, quality-by-design approach.

COVID-PACT is a multicenter, randomized, open-label, 2 x 2 factorial design trial of full-dose anticoagulation vs. standard-dose prophylactic anticoagulation and antiplatelet therapy vs. no antiplatelet therapy on the risk of venous or arterial thrombotic events in ICU patients with COVID-19.  Study patients will be followed until their 28th day or hospital discharge, whichever comes first.

TIMI 67 will evaluate the efficacy, safety and tolerability of AMG 890 (a small, interfering RNA) in subjects with elevated lipoprotein(a).

DAPA ACT HF-TIMI 68 is an investigator-initiated, randomized, double-blind, placebo-controlled trial in patients with heart failure with reduced ejection fraction (LVEF ≤40%) who have been stabilized during hospitalization for acute heart failure, evaluating the effect of in-hospital initiation of dapagliflozin on the clinical outcome of cardiovascular death or worsening heart failure.

GOLDILOX-TIMI 69 is a Phase IIB, Randomized, Double-Blinded, Placebo-Controlled Trial To Evaluate the Efficacy and Safety of MEDI6570 (a fully human monoclonal antibody against LOX-1) in Participants with a Prior Myocardial Infarction, Persistent Inflammation, and Elevated N-Terminal Prohormone Brain Natriuretic Peptide.

TRANSLATE-TIMI 70 is a phase 2b trial testing multiple doses of vupanorsen, an antisense oligonucleotide (ASO) against angiopoietin-like 3 (ANGPTL3) mRNA, for safety and efficacy in non-HDL-C lowering.

TIMI Risk Score calculators

There are several TIMI Risk Score calculators, each designed for a particular group.

TIMI Risk Score for UA/NSTEMI

In patients with UA/NSTEMI, the TIMI risk score is a simple prognostication scheme that categorizes a patient's risk of death and ischemic events and provides a basis for therapeutic decision making.[1]

  • Age ≥ 65 years? Yes (+1)
  • ≥ 3 Risk Factors for CAD*? Yes (+1)
  • Known CAD (stenosis ≥ 50%)? Yes (+1)
  • ASA Use in Past 7d? Yes (+1)
  • Severe angina (≥ 2 episodes w/in 24 hrs)? Yes (+1)
  • ST changes ≥ 0.5mm? Yes (+1)
  • + Cardiac Marker? Yes (+1)

*Risk factors include family history of CAD, hypertension, hypercholesterolemia, diabetes, or being a current smoker.

What Does This Score Mean?

% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.[2]

1 Point 5% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
2 Points 8% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
3 Points 13% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
4 Points 20% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
5 Points 26% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
6 Points 41% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.
7 Points 41% risk at 14 days of: all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization.

'TIMI risk' estimates mortality following acute coronary syndromes. TIMI risk can be calculated on the TIMI website under "Clinical Calculators."[3]

The TIMI Risk Score for STEMI is also useful for patients with known STEMI. Though these patients have a clear protocol - normally thrombolysis or Percutaneous coronary intervention - and are already high risk for mortality, the TIMI Risk Score for STEMI provide risk stratification which helps treatment decisions after acute issues have been resolved.[4]

TIMI Risk Score for STEMI
  • Age 65–74 years? Yes (+2)
  •     – or –
  • Age ≥75 years? Yes (+3)
  • Diabetes, Hypertension or Angina? Yes (+1)
  • Systolic BP < 100 mmHg? Yes (+3)
  • Heart rate > 100? Yes (+2)
  • Killip Class II-IV (JVD or any pulmonary exam findings of CHF)? Yes (+2)
  • Weight < 67 kg (147.7 lbs)? Yes (+1)
  • Anterior ST Elevation or LBBB? Yes (+1)
  • Time to treatment > 4 hours? Yes (+1)

What Does This Score Mean?

0 Points 0.8% risk of all-cause mortality at 30 days.
1 Point 1.6% risk of all-cause mortality at 30 days.
2 Points 2.2% risk of all-cause mortality at 30 days.
3 Points 4.4% risk of all-cause mortality at 30 days.
4 Points 7.3% risk of all-cause mortality at 30 days.
5 Points 12.4% risk of all-cause mortality at 30 days.
6 Points 16.1% risk of all-cause mortality at 30 days.
7 Points 23.4% risk of all-cause mortality at 30 days.
8 Points 26.8% risk of all-cause mortality at 30 days.
9 Points 35.9% risk of all-cause mortality at 30 days.
10 Points 35.9% risk of all-cause mortality at 30 days.
11 Points 35.9% risk of all-cause mortality at 30 days.
12 Points 35.9% risk of all-cause mortality at 30 days.
13 Points 35.9% risk of all-cause mortality at 30 days.
14 Points 35.9% risk of all-cause mortality at 30 days.
15 Points 35.9% risk of all-cause mortality at 30 days.
16 Points 35.9% risk of all-cause mortality at 30 days.

TIMI Risk Score for HF in Diabetes
  • Prior heart failure? Yes (+2)
  • History of atrial fibrillation? Yes (+1)
  • Coronary artery disease? Yes (+1)
  • eGFR < 60 ml/min/1.73*m2? Yes (+1)
  • Urine albumin-to-creatinine ratio >300 mg/g? Yes (+2)
  •     – or –
  • Urine albumin-to-creatinine ratio 30–300 mg/g? Yes (+1)

What Does This Score Mean?

0 Points Incidence rate of hospitalization for heart failure: 2.4 (per 1000 patient-years)
1 Point Incidence rate of hospitalization for heart failure: 4.4 (per 1000 patient-years)
2 Points Incidence rate of hospitalization for heart failure: 13.1 (per 1000 patient-years)
3 Points Incidence rate of hospitalization for heart failure: 28.7 (per 1000 patient-years)
4 Points Incidence rate of hospitalization for heart failure: 56.1 (per 1000 patient-years)
5 Points Incidence rate of hospitalization for heart failure: 56.1 (per 1000 patient-years)
6 Points Incidence rate of hospitalization for heart failure: 56.1 (per 1000 patient-years)
7 Points Incidence rate of hospitalization for heart failure: 56.1 (per 1000 patient-years)
8 Points Incidence rate of hospitalization for heart failure: 56.1 (per 1000 patient-years)

TIMI Risk Score for 2°P
  • Congestive heart failure? Yes (+1)
  • Hypertension? Yes (+1)
  • Age 75 or older? Yes (+1)
  • Diabetes? Yes (+1)
  • Prior stroke? Yes (+1)
  • Prior CABG? Yes (+1)
  • Peripheral arterial disease? Yes(+1)
  • Renal dysfunction with eGFR < 60? Yes (+1)
  • Current smoking? Yes (+1)

What Does This Score Mean?

TIMI Grade Flow

'TIMI Grade Flow' is a scoring system from 0-3 referring to levels of coronary blood flow assessed during percutaneous coronary angioplasty:

  • TIMI 0 flow (no perfusion) complete blockage - absence of any antegrade flow (forward flow) beyond a coronary occlusion.
  • TIMI 1 flow (penetration without perfusion) is faint antegrade coronary flow beyond the occlusion, with incomplete filling of the distal coronary bed.
  • TIMI 2 flow (partial reperfusion) is delayed or sluggish antegrade flow with complete filling of the distal territory.
  • TIMI 3 is normal flow which fills the distal coronary bed completely

References
  1. Elliott M. Antman, MD; Marc Cohen, MD; Peter J. L. M. Bernink, MD; Carolyn H. McCabe, BS; Thomas Horacek,MD,"The TIMI Risk Score for Unstable Angina/Non–ST Elevation MI", JAMA, 2000
  2. Antman, Elliott M.; Cohen, Marc; Bernink, Peter J. L. M.; McCabe, Carolyn H.; Horacek, Thomas; Papuchis, Gary; Mautner, Branco; Corbalan, Ramon; Radley, David; Braunwald, Eugene (2000). "The TIMI Risk Score for Unstable Angina/Non–ST Elevation MI". JAMA. 284 (7): 835–42. doi:10.1001/jama.284.7.835. ISSN 0098-7484. PMID 10938172.
  3. TIMI Risk Score
  4. David A. Morrow, et al. TIMI Risk Score for ST-Elevation Myocardial Infarction: A Convenient, Bedside, Clinical Score for Risk Assessment at Presentation: An Intravenous nPA for Treatment of Infarcting Myocardium Early II Trial Substudy Circulation.2000; 102: 2031-2037 doi: 10.1161/01.CIR.102.17.2031

Further reading
  • Chesebro, J. H., G. Knatterud, R. Roberts, J. Borer, L. S. Cohen, J. Dalen, H. T. Dodge, C. K. Francis, D. Hillis, and P. Ludbrook. "Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A Comparison between Intravenous Tissue Plasminogen Activator and Intravenous Streptokinase. Clinical Findings through Hospital Discharge." Circulation 76.1 (1987): 142–54. American Heart Association - Circulation. Web. 17 July 2015.
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